The present invention relates to N-aryl-homopiperazinyl-cyclohexylamine derivatives having pharmacological activity, and to their use in the treatment of diseases affected by disorders of the serotonin affected neurological systems, such as depression and anxiety.
Pharmaceuticals with enhance serotonergic neurotransmission are of useful benefit for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affection drugs operated through a variety of physiological functions which endowed them with several side effect liabilities. The more currently prescribed drugs, the selective serotonin reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic serotonin transport carrier.
Wustrow et al. have disclosed a series of 3-[[4-aryl-1-piperazinyl)alkyl]cyclohexyl]-1H-indoles as dopamine D2 partial agonists in J. Med. Chem. 1997, 40, 250.
Cipollina et al. have disclosed a series of indolylcycloalkylamines as serotonergic vasoconstrictors for the treatment of vascular or migraine headaches in European Patent Application EP 666258.
Shiota et al. have disclosed a series of cyclic diarylalkyl derivatives (including aryl homopiperazines) as chemokine receptor antagonists in PCT Int. Patent Application WO 9744329. Hidaka et al. have disclosed a series of aryl cyclic diamines (including aryl homopiperazines) as anti-ulcer agents in U.S. Pat. No. 5,244,895 and European Patent Application 513691. Hidaka et al. have also disclosed a series of aryl cyclic diamines (including aryl homopiperazines) as blood vessel relaxants in U.S. Pat. Nos. 5,081,246; 5,216,150 and 5,245,034.
The present invention provides N-aryl-homopiperazinyl-cyclohexylamine derivatives having pharmacological activity as 5-HT transporters, and to their use in the treatment of diseases affected by disorders of the serotonin affected neurological systems, such as depression and anxiety.
In accordance with this invention there, is provided a group of compounds represented by the formula I: 
wherein:
Ar is an aryl group of 4 to 10 carbon atoms or a heteroaryl group of 4 to 10 carbon atoms, the aryl or heteroaryl group being optionally substituted by from 1 to 3 groups selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, thioalkyl of 1 to 6 carbon atoms, perfluoralkyl of 1 to 6 carbon atoms, hydroxy, nitro, amino, or cyano;
R1 and R2 are independently, hydrogen, straight chain alkyls of 1 to 12 carbon atoms, branched alkyls of 3 to 10 carbon atoms or cycloalkyls of 3 to 10 carbon atoms;
R3 is H, straight chain alkyl of 1 to 12 carbon atoms, branched alkyl of 3 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, halogen, alkoxy group of 1 to 12 carbon atoms, haloalkyl of 1 to 12 carbon atoms, hydroxy, nitro, nitrile, amino, cyano, carboxy, alkoxycarbonyl of 1 to 12 carbon atoms, alkylcarbonyl of 1 to 12 carbon atoms, aminocarbonyl and alkylaminocarbonyl of 1 to 12 carbon atoms; and all crystalline forms or a pharmaceutically acceptable salt thereof.
Among the preferred compounds of this invention are those of formula I wherein:
Ar is an aryl group of 5 or 6 carbon atoms or a heteroaryl group of 5 to 10 carbon atoms;
R1 and R2 are independently, H, straight chain alkyls of 1 to 8 carbons or branched alkyls of 3 to 8 carbon atoms;
R3 is H, straight chain alkyl of 1 to 8 carbon atoms, branched alkyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, halogen, alkoxy of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, haloalkoxy or 1 to 6 carbon atoms, hydroxy, nitro, nitrile, amino, cyano, carboxy, alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, aminocarbonyl and alkylaminocarbonyl of 1 to 6 carbon atoms;
and all crystalline forms or a pharmaceutically acceptable salt thereof.
In still more preferred aspects of the invention are provided compounds of formula I wherein:
Ar is an aryl group of 6 carbon atoms or a heteroaryl group or a heteroaryl group of 5 to 10 carbon atoms;
R1 and R2, are independently, H, straight chain alkyls of 1 to 3 carbons or branched alkyls of 3 to 6 carbon atoms;
R3 is H, halogen, cyano CONH2, or CO2H;
and all crystalline forms or a pharmaceutically acceptable salt thereof.
Alkyl, whether used alone or as part of another group include straight and branched chain alkyl groups containing from 1 to 12 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, i-butyl and t-butyl are encompassed by the term alkyl. In some embodiments of the present invention alkyl may refer to substituted or unsubstituted alkyl. Carbon number refers to carbon backbone and does not include carbon atoms of substituents such as alkoxy substitutions and the like. Halogen, as used herein means chlorine, bromine, iodine and fluorine.
Aryl, as used herein refers to single or multiple 4 to 10 membered aromatic ring radicals including but not limited to phenyl, benzyl, naphthalene, anthracene, phenanthrene, indene and indacene. Preferred are phenyl, benzyl and naphthalene. In some embodiments of the present invention, the aryl group may be substituted by alkyl groups, perfluoroalkyl groups, preferably trifluoromethyl groups, alkoxy groups, and halogens.
Heteroaryl as used herein refers to single or multiple 4 to 10 membered aromatic ring radicals having from 1 to 3 heteroatoms selected from S, O or N including, but not limited to, furan, thiophene, pyrrole, imidazole, oxazole, thiazole, isoxazole, pyrazole, isothiazole, oxadiazole, triazole, thiadiazole, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, napthyridine, pteridine, pyridine, pyrazine, pyrimidine, pyridazine, pyran, triazine, indole, isoindole, indazole, indolizine, and isobenzofuran. Preferred heteroaryls include furan, thiophene, pyrrole, imidazole, oxazole, thiazole, isoxazole, pyrazole, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, quinolizine, quinoline, and isoquinoline. More preferred heteroaryls include furan, thiophene, imidazole, isoxazole, quinoline and pyrazole. In some embodiments of the present invention, the heteroaryl group is substituted.
Preferably, the substituted aryl group is substituted with from 1 to 3 groups. The substituted heteroaryl group is preferably substituted with 1 to 3 groups and more preferably 1 to 2 groups. Alkyl and cycloalkyl groups may also be substituted. Suitable substitutions include, but are not limited to halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, nitro, nitrile, amino, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, alkoxycarbonylalkyl and alkylcarbonyloxy.
Among the most preferred compounds of the present invention are:
3-{4-[4-(2-Methoxy-phenyl)-[1,4]diazepan-1-yl]-cyclohexyl}-1H-indole;
8-{4-[4-(1H-Indol-3-yl)-cyclohexyl-]-[1,4]diazepan-1-yl}-quinoline;
3-{4-[4-(2-Methoxy-phenyl)-[1,4]diazepan-1-yl]-cyclohexyl}-5-fluoro-1H-indole;
3-{4-[4-(2-Methoxy-phenyl)-[1,4]diazepan-1-yl]-cyclohexyl}-5-cyano-1H-indole;
3-{4-[4-(2-Methoxy-phenyl)-[1,4]diazepan-1-yl]-cyclohexyl}-6-fluoro-1H-indole;
8-{4-[4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-[1,4]diazepan-1-yl}-quinoline;
8-{4-[4-(5-Cyano-1H-indol-3-yl)-cyclohexyl]-[1,4]diazepan-1-yl}-quinoline;
8-{4-[4-(6-Fluoro-1H-indol-3-yl)-cyclohexyl]-[1,4]diazepan-1-yl}-quinoline;
3-{4-[4-(3-Trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-cyclohexyl}-5-fluoro-1H-indole;
3-{4-[4-(3-Trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-cyclohexyl}-5-cyano-1H-indole;
3-{4-[4-(3-Trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-cyclohexyl}-6-fluoro-1H-indole;
or a pharmaceutically acceptable salt of one of these compounds.
It is understood that the definition of the compounds of formula I, when R1, R2 or R3 contain asymmetric carbons, encompass all possible stereoisomers and mixtures thereof which possess the activity discussed below. In particular, it encompasses racemic modifications and any optical isomers which possess the indicated activity. Optical isomers may be obtained in pure form by standard separation techniques.
Pharmaceutically acceptable salts are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, succinic, maleic, malonic, oxalic, fumaric, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids. Where R1, R2 or R4 contain a carboxyl group, salts of the compounds of this invention may be formed with bases such as alkali metals (Na, K, Li) or the alkaline earth metals (Ca or Mg).
As mentioned previously, the compounds of formula I have affinity for the 5-HT reuptake transporter and are useful in the treatment of diseases affected by disorders of the serotonin affected neurological systems, such as depression and anxiety, sleep disorders, sexual dysfunction, alcohol and cocaine addiction, cognition enhancement and related problems. The present invention accordingly also provides pharmaceutical compositions which comprise a compound of this invention in combination or association with a pharmaceutically acceptable carrier or excipient.
The compositions are preferably adapted for oral or subcutaneous administration. However, they may be adapted for other modes of administration.
The compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent and the like. They are formulated in conventional manner, for example, in a manner similar to that use for known antihypertensive agents, diuretics and xcex2-blocking agents. Applicable solid carriers or excipients can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintergrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
In order to obtain consistency of administration, it is preferred that a composition of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules and powders in sachets or vials. Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg. Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg. Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
Generally, the compounds of formula I are conveniently synthesized as described below:
In accordance with the present invention, compounds of formula I may be prepared to the following Scheme I. 
Thus, compound of formula II is reacted with compound of formula III, acetic acid in dichloroethane at 23xc2x0 C. to give a compound of formula I in accordance with the procedure described by Abdel-Magid, Carson, Harris, Maryanoff and Shah in J. Org. Chem. 1996, 61, 3849.
In accordance with the present invention, compounds of formula II may be prepared to the following Scheme II. 
Thus compounds of formula IV are reacted with 1,4-cyclohexanedione monoethylene ketal, potassium hydroxide in methanol at 65xc2x0 C. to give compounds of formula V as described by Wustrow et al. in J. Med. Chem. 1997, 40, 250. Hydrogenation to compounds of formula VI can be realized by treatment in suitable solvents such as an alcohol, but not limited to EtOH with H2 and 5% Pd/C. Hydrolysis to compounds of formula III can be carried out using 1N HCl in a 1:1 mixture of THF and water.
In accordance with the present invention, compounds of formula II may be prepared to the following Scheme III. 
Thus the compound of formula VII is treated with (Boc)2O in a suitable solvent such as chloroform, THF or an alcohol, but not limited to MeOH to give the compound of formula VII. Conversion to compounds of formula IX can be realized by treatment with an aryl bromide, catalytic Pd2dba3, catalytic BINAP, NaOt-Bu, in toluene at 80xc2x0 C. according to the procedure of Buchwald et al. in Anew. Chem., Int. Ed. Engl. 1995, 34, 1348. Deprotection to give compounds of formula II can be accomplished via treatment with TFA in CH2Cl2 at 23xc2x0 C.
The present invention further provides a compound of the invention for use as an active therapeutic substance. Compounds of formula (I) are of particular use in the treatment of diseases affected by disorders of the serotonin.
The present invention further provides a method of treating depression and anxiety in mammals including man, which comprises administering to the afflicted mammal an effective amount of a compound or a pharmaceutical composition of the invention.